Antibodies specific for human immunodeficiency virus-1 (HIV-1), the causative agent of acquired immunodeficiency syndrome (AIDS), are found in the sera of HIV-infected individuals (Sarngadharan et al. (1984) Science 224,506-508; Schupbach et al. (1984) Science 224,503-505; Chang et al. (1985) Biotechnoloy 3, 905-911; Kenealy et al. (1987) AIDS Research and Human Retroviruses 3, 95-105). The level of serum antibodies that block HIV-1 proliferation (HIV-neutralizing antibodies) or block the fusion of HIV-infected and noninfected cells in cell culture (fusion-blocking antibodies) is relatively low when compared to the overall humoral response to the virus (i.e., total levels of HIV-specific antibodies) (Weiss et al. (1985) Nature 316,69-74; Robert-Guroff et al. (1985) Nature 316,72-74; Weiss et al. (1986) Nature 324,572-575). The role of HIV-neutralizing and fusion-blocking antibodies in the pathogenesis of HIV-1 infection and the structure of the epitopes responsible for this biological activity remain to be determined. The exterior envelope glycoprotein of HIV-1 (gp120) is known to bind human neutralizing antibodies and has been used as an immunogen capable of eliciting HIV-neutralizing antibodies in animals (Lasky et al. (1986) Science 233,209-212; Matthews et al. (1986) Proc. Natl. Acad. Sci. USA 83,9709-9713; Robey et al. (1986) Proc. Natl. Acad. Sci. USA 84,7023-7927). Notably, these neutralizing antibodies are reported to be type-specific, i.e., the antibodies only block proliferation of the HIV-1 subtype or isolate from which the immunogen was derived.
A number of HIV-1 peptides and proteins have been identified which elicit neutralizing antibodies in animals. These include synthetic peptides corresponding to sequences from the gag-coded protein, the env-coded transmembrane protein (gp41), and several peptides corresponding to conserved regions of the env-coded gp120 protein (Putney et al. (1986) Science 234,1392-1395; Sarin et al. (1986) Science 232,1135-1137; Kennedy et al. (1987) J. Biol. Chem. 262,5769-5774; Taylor et al. (1987) Proc. Natl. Acad. Sci. USA 84,2951-2955; Chanh et al. (1986) EMBO J. 5,3065-3071; Ho et al. (1987) J. of Virol. 61,2024-2028). Particularly high levels of neutralizing and fusion-blocking antibodies have been shown to be induced in animals by two recombinant proteins. One of these is a glycosylated full length env-coded protein produced using an insect cell expression system, designated gp160 (Rusehe et al. (1987) Proc. Natl. Acad. Sci. USA 84,6924-6928) and a second is a nonglycosylated Escherichia coli produced protein, designated PB1, representing a region of gp120 (amino acids number 288 to 472 of HIV-1 IIIB) (Putney et al. (1986) Science 234,1392-1395). In spite of the strong antibody responses using these proteins as immunogens, the neutralizing activity remained restricted to and specific for the HIV-1 subtype or isolate from which the immunogen was derived, i.e., IIIB.
Recombinant proteins PE3 (corresponding to the amino terminus of the env-coded gp120) and ENV9 (corresponding to the carboxyl-terminus of gp120 and most of gp41) did not elicit measurable levels of neutralizing activity (Putney et al. (1986) Science 234,1392-1395), whereas PB1 was capable of inducing levels of neutralizing and fusion-blocking antibodies comparable to or greater than those elicited using the recombinant gp160 (Rusche et al. (1987) Proc. Natl. Acad. Sci. USA 84,6924-6928).